Objective. Spondyloarthritides (SpA) occur in 1% of the population and include ankylosing spondylitis (AS) and arthropathy of inflammatory bowel disease (IBD), with characteristic spondylitis, arthritis, enthesitis, and IBD. Genetic studies implicate interleukin-23 (IL-23) receptor signaling in the development of SpA and IBD, and IL-23 overexpression in mice is sufficient for enthesitis, driven by entheseal-resident T cells. However, in genetically prone individuals, it is not clear where IL-23 is produced and how it drives the SpA syndrome, including IBD or subclinical gut inflammation of AS. Moreover, it is unclear why specific tissue involvement varies between patients with SpA. We undertook this study to determine the location of IL-23 production and its role in SpA pathogenesis in BALB/c ZAP-70(W163C)-mutant (SKG) mice injected intraperitoneally with beta-1,3-glucan (curdlan).

Formatted abstract

Objective: Spondyloarthropathies (SpA) occur in 1% of the population, and include ankylosing spondylitis and arthropathy of inflammatory bowel disease (IBD), with characteristic spondylitis, arthritis, enthesitis and IBD. Genetic studies implicate IL-23 receptor signaling in the development of SpA and IBD, and IL-23 over-expression in mice is sufficient for enthesitis, driven by entheseal-resident T cells. However in genetically-prone individuals, it is not clear where IL-23 is produced and how it drives the SpA syndrome, including IBD or sub-clinical gut inflammation of ankylosing spondylitis. Moreover, it is unclear why specific tissue involvement varies between patients with SpA. We determined the location of IL-23 production and its role in SpA pathogenesis in BALB/c ZAP70W163C-mutant (SKG) mice injected i.p. with beta-1,3-glucan (curdlan).

Methods: Eight weeks after curdlan injection of wild type or IL-17-deficient SKG or BALB/c mice, pathology was scored in tissue sections. Mice were treated with anti-IL-23 or anti-IL22. Cytokine production and endoplasmic reticulum stress were determined in affected organs. Results: In curdlan-treated SKG mice arthritis, enthesitis and ileitis were IL-23-dependent. Enthesitis was specifically dependent on IL-17A and IL-22. IL-23 was induced in the ileum, where it amplified endoplasmic reticulum stress, goblet cell dysfunction and pro-inflammatory cytokine production. IL-17A was pathogenic while IL-22 was protective of ileitis. IL-22+CD3- innate-like cells were increased in lamina propria of ileitis-resistant BALB/c mice, which developed ileitis after curdlan and anti-IL-22.